Molecular and Clinical Predictors of Improvement in Progression‐free Survival with Maintenance PARP Inhibitor Therapy in Women with Platinum‐sensitive, Recurrent Ovarian Cancer: A Meta‐analysis
Open accessAbstract
BACKGROUND: The authors performed a meta-analysis to better quantify the benefit of maintenance poly(ADP-ribose) polymerase inhibitor (PARPi) therapy to inform practice in platinum-sensitive, recurrent, high-grade ovarian cancer for patient subsets with the following characteristics: germline BRCA mutation (gBRCAm), somatic BRCA mutation (sBRCAm), wild-type BRCA but homologous recombinant-deficient (HRD), homologous recombinant-proficient (HRP), and baseline clinical prognostic characteristics. METHODS: Randomized trials comparing a PARPi versus placebo as maintenance treatment were identified from electronic databases. Treatment estimates of progression-free survival were pooled across trials using the inverse variance weighted method. RESULTS: Four trials included 972 patients who received a PARPi (olaparib, 31%; niraparib, 35%; or rucaparib, 34%) and 530 patients who received placebo. For patients who had germline BRCA1 mutation (gBRCAm1) (N = 471), the hazard ratio (HR) was 0.29 (95% CI, 0.23-0.37); for those who had germline BRCA2 mutation (gBRCAm2) (N = 236), the HR was 0.26 (95% CI, 0.17-0.39); and, for those who had sBRCAm (N = 123), the HR was 0.22 (95% CI, 0.12-0.41). The treatment effect was similar between the gBRCAm and sBRCAm subsets (P = .48). In patients who had wild-type BRCA HRD tumors (excluding sBRCAm; N = 309), the HR was 0.41 (95% CI, 0.31-0.56); and, in those who had wild-type BRCA HRP tumors (N = 346), the HR was 0.64 (95% CI, 0.49-0.83). The relative treatment effect was greater for the BRCAm versus HRD (P = .03), BRCAm versus HRP (P < .00001), and HRD versus HRP (P < .00001) subsets. There was no difference in benefit based on age, response after recent chemotherapy, and prior bevacizumab. CONCLUSIONS: In platinum-sensitive, recurrent, high-grade ovarian cancer, maintenance PARPi improves progression-free survival for all patient subsets. PARPi therapy has a similar magnitude of benefit for sBRCAm and gBRCAm. Although patients with BRCAm derive the greatest benefit, the absence of a BRCAm or HRD could not be used to exclude patients from maintenance PARPi therapy.
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Functional analyses, alongside molecular assays, are required to confirm the predicted response of women with ovarian cancer to PARP inhibitors such as olaparib, niraparib and rucaparib.
“Functional analyses, alongside molecular assays, are required to confirm the predicted response of women with ovarian cancer to PARPis such as the FDA-approved drugs olaparib, niraparib and rucaparib (Dickson et al., 2021; Lee et al., 2021; Valabrega et al., 2021).”
From Three-dimensional modelling of ovarian cancer: from cell lines to organoids for discovery and personalized medicine (2022) · cites this paper as Lee et al., 2021
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Yee, C., Dickson, K.-A., Muntasir, M. N., Ma, Y., & Marsh, D. J. (2022) · Frontiers in Bioengineering and Biotechnology · doi:10.3389/fbioe.2022.836984 · Cited by 66 · see citing works
- Authors
- Lee, C. K., Friedlander, M. L., Tjokrowidjaja, A., Ledermann, J. A., Coleman, R. L., Mirza, M. R., Matulonis, U. A., Pujade‐Lauraine, E., Bloomfield, R., Goble, S., Wang, P., Glasspool, R. M., Scott, C. L., & the Gynecologic Cancer Intergroup Meta‐Analysis Committee
- Affiliations
- The University of Sydney (AU)
- UNSW Sydney (AU)
- University College London (GB)
- The University of Texas MD Anderson Cancer Center (US)
- Copenhagen University Hospital (DK)
- Dana-Farber Cancer Institute (US)
- Université Paris Descartes, Assistance Publique–Hôpitaux de Paris Paris France
- AstraZeneca (United Kingdom) (GB)
- Clovis Oncology (United States) (US)
- GlaxoSmithKline (United States) (US)
- National Health Service (GB)
- The University of Melbourne (AU)
- ORCID
- Venue
- Cancer
- Publisher
- Wiley
- Published
- 2021-03-19
- Volume
- 127
- Issue
- 14
- Pages
- 2432-2441
- ISSN
- 0008-543X (ISSN-L)
- 1097-0142
- OpenAlex
- W3136213266
- Cited by
- 36
- References
- 30
- Citations by year
- 2026: 4 · 2025: 7 · 2024: 7 · 2023: 10 · 2022: 7 · 2021: 1
- FWCI
- 2.27
- Type
- journal article
- Language
- en
- Open access
- green
- discovery.ucl.ac.uk
- Locations
- Cancer (publishedVersion)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Minerva Access (University of Melbourne) (submittedVersion)
- Topics
- Health Sciences › Medicine › Oncology › PARP inhibition in cancer therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › BRCA gene mutations in cancer
- Health Sciences › Medicine › Reproductive Medicine › Ovarian cancer diagnosis and treatment
- Keywords
- PARP inhibitors, maintenance therapy, recurrent ovarian cancer, platinum-sensitive ovarian cancer, progression-free survival, germline BRCA1 mutation, germline BRCA2 mutation, somatic BRCA mutations, homologous recombination deficiency, olaparib, niraparib, rucaparib, predictive biomarkers, treatment response
- MeSH terms
- Poly(ADP-ribose) Polymerase Inhibitors, Progression-Free Survival, Clinical Trials as Topic, Female, Humans, Neoplasm Recurrence, Local, Ovarian Neoplasms, Treatment Outcome, Maintenance Chemotherapy
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